This invention relates to novel method to prepare substituted 2-(pyridin-2-ylamino)-pirido[2,3-d]pyrimidin-7-ones has the formula (herein to as “Formula 1”),
wherein R1 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C3-C7 cycloalkyl;    R3 is hydrogen, OH, —NH2, aryl, C1-C8 alkyl, C3-C7 cycloalkyl, or C3-C7-heterocyclyl;    R5, is —(CR7R8)mNR7 or —(CR7R8)m— (3 to 10 member heterocycle comprising a N ring atom), wherein m is 0, 1, 2 or 3;    and each R7 and R8 is independently H or C1-C6 alkyl;or a pharmaceutically acceptable salt thereof.
In particular, the present invention relates to novel methods for the preparation of the isethionate salt forms of compound 6-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride (also referred to as “Compound 1”),
as well as its intermediates. Compound 1 is described in U.S. Pat. No. 6,936,612, the disclosure of which is hereby incorporated in its entirety. This compound is a protein kinase inhibitor and represents a synthetic, small molecule inhibitor capable of modulating cell cycle control.
A method of preparing Compound 1 is disclosed as Example 36 of U.S. patent application Ser. No. 6,936,612. Methods of preparing the isethionate salt forms of Compound 1 are disclosed in Examples 1-13 of WO 2005/005426. These methods are for synthesis of small quantities of the salt forms of Compound 1 and are not designed for commercial scale-up. Therefore, a preparation of the salt forms for CDK inhibitor 6-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride which is cost-efficient, scaleable and productive is highly desirable.